Trends in Neurosciences
ReviewThe Autophagy–Lysosomal Pathway in Neurodegeneration: A TFEB Perspective
Section snippets
Subtypes and Machinery of Autophagy
Autophagy or autophagocytosis is derived from the Greek words auto, ‘self’, and phagein, ‘to eat’. This so-called self-eating refers to a basic catabolic mechanism/degradation pathway that involves the delivery of cytoplasmic cargo to the lysosome. Autophagy is typically categorized into three groups based on the particular physiological role of the process, the mode of cargo delivery, and the pathway. These groups are as follows: macroautophagy (see Glossary; herein referred to as autophagy),
Mammalian (or Mechanistic) Target of Rapamycin (mTOR)
The best-studied regulator of mammalian autophagy is mTOR (Figure 2). Through mTOR, we have several well-defined pathways of the regulation of autophagy (Box 2).
Role of TFEB in the ALP
Coordination of the multiple steps in the ALP and the need to adapt this process to different physiological and pathological conditions requires the existence of a master regulator. One such global regulator of the ALP is TFEB, a member of the MiT family of transcription factors that also includes TFE3, TFEC, and MITF (Box 3) [29]. TFEB
Huntington's Disease
HD is a neurodegenerative disease caused by expansion of a CAG trinucleotide repeat in the first exon of the huntingtin (HTT) gene. This results in a protein that contains an expanded poly-glutamine (polyQ) tract, leading to misfolding into a pathogenic conformation. Despite the relatively simple genetic cause of HD, the etiology of the disease is vastly unknown. HTT is a large protein with ubiquitous cellular localization. Its normal function remains poorly defined, complicating understanding
Concluding Remarks
Overwhelming evidence supports a crucial role of the ALP in the degradation of misfolded proteins that accumulate in numerous neurodegenerative disorders. Enhancing the ALP thus holds therapeutic promise in the treatment of neurodegenerative diseases. TFEB has emerged as a potent activator of the ALP by coordinating autophagy induction with lysosomal biogenesis. The fact that TFEB can be modulated by phosphorylation and activated through kinase inhibition, which is potentially druggable, makes
Acknowledgments
We thank members of the laboratories of H.Z. and A.B. for stimulating discussions. Results presented from the our laboratory were supported by R01 grants from the National Institutes of Health (NIH) (NS093652, AG020670, and NS076117) and the Belfer Neurodegeneration Consortium to H.Z., and the Italian Telethon Foundation, the Beyond Batten Disease Foundation, the European Research Council, and the NIH (R01 NS 078072-01A1) to A.B.
Glossary
- Autophagy–lysosomal pathway (ALP)
- autophagy is a conserved degradation pathway. Three types of autophagy transport substrates to the lysosome where lysosomal enzymes degrade substrates.
- Autophagy-related genes (ATGs)
- a class of genes encoding proteins facilitating the process of the ALP.
- Chaperone-mediated autophagy
- the specific degradation of protein substrates with a pentapeptide KFERQ motif.
- Coordinated lysosomal expression and regulation (CLEAR) network
- the lysosomal gene network regulated by
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Equal contribution.